Adverse Drug Reactions and Drug Safety Flashcards
Dose-response curve:
a number of increasing doses of a drug are given to the same subject and the increase in response for each dose is measured (graded in increments) allowing determination of the maximal effect of the drug (Emax). ED50 is the dose that produces 50% of the maximal response possible in an individual
Population dose-response curve (quantal):
characterize pharmacologic responses that are all-or-nothing events (not graded) in a population of subjects (not an individual), generated by arbitrarily defining some specific therapeutic effect (ie: relief of headache) and then determining the minimum dose to produce this response in each member of the population. Single given dose of drug in an individual test subject will either bring about the response or not (all-or-nothing). Data is plotted as fraction of population that response at each dose of drug vs. the log of dose administered. Quantal curves are not used to determine Emax (like dose-response). ED50 is the dose that initates the response in 50% of the test population.
Degree of risk evaluated by
comparing the quantal dose-response curves for the desirable and toxic effects. Generated in the same way except for that the all-or-nothing effect is a toxic effect (side effect, death) and TD50 is the dose that produces an undesirable side effect in 50% of subjects and LD50 is the lethal dose that causes death in 50% of subjects.
To compare the dosage necessary for desired effect vs. dose with undesirable effect use: Therapeutic index:
compares midpoint in the population (ED50 and LD50)
a. TI= LD50/ED50
b. The higher the TI, the safer the drug, clinically used drug are ˃10-20
To compare the dosage necessary for desired effect vs. dose with undesirable effect use: Standard safety margin:
looks at the extremes in the population (ED50 and LD1)
a. SSM= [(LD1/ED99)-1] x 100
b. More conservative measure that TI, more reliable if pt response to therapy to specific drug varies, takes into account the extremes, SSM can be negative
Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing: A
controlled studies show no risk, possibility of harm to fetus is remote, KCl
Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing: B
no evidence of risk in humans (opioids, acetaminophen, ondanstron, thiazide diuretics)
Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing: C
risk cannot be ruled out (pseudoephedrine, antidepressants)
Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing: D
positive evidence of human fetal risk, but potential benefits may outweigh the risks (in a life-threatening situation or serious disease) (oral anticoags, ACE inhibitors, diazepam-lorazepan, alprazolam, paroxetine)
Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing: X
contraindicated in pregnancy, risks involved in the use of drug clearly outweighs the benefits, (HMG CoA reductase inhibitor-statins, isotretinoin)
Pharmacokinetic effects on absorption:
decreased motility=decreased absorption rate=lower peak plasma drug levels (doesn’t change bioavailability), increases in the rate of absorption less important clinically. Physiochemical inactivation via change in pH or formation of insoluble complexes reduced bioavailability.
Pharmacokinetic effects on distribution
protein binding, displacement interactions, competitive binding may increase amount of free drug, cellular distribution interactions. Displacement of 1st drug from protein by 2nd drug results in increased levels of unbound-free 1st drug (total drug unchanged)
Pharmacokinetic effects on metabolism
metabolic rate increased by inducers –> reduced +/- subtherapeutic levels, rate decreased by inhibitors –> increased and possibly toxic levels. Most interactions occur via effects on cytochrome P450 (oxidation Phase 1 reactions)
Pharmacokinetic effects on excretion
most excretion interactions occur in the kidneys and include:
- glomerular filtratiuon rate (decreased by nephrotoxic drugs –> increased Cp, increased by displacement from plasma proteins –> decreased Cp)
- tubular secretion (decreased by competition for active transport –> increased Cp)
- change in tubular reabsorption via increase in urine pH (decreased for weak acid drugs –> decreased Cp, increased for weal base drugs –> increased Cp)
- change in tubular reabsorption via decrease in urine pH (increased for weak acid drugs –> increased Cp, decreased for weak base drugs –> increased Cp)
Pharmacodynamic: antagonistic effects:
Two drugs with opposite pharmacologic effects given together
1. beta-blocker (hypertension) + beta-agonist (asthma) –> bronchospasm
